Center News Magazine: Sifting Through the Prostate Cancer Genome

Friday, October 1, 2010

(From left) The first four authors of the June 24 Cancer Cell study, Barry Taylor, Anuradha Gopalan, Haley Hieronymous, and Nikolaus Schultz.

A team of clinicians and computational biologists have compiled the largest catalog to date of genetic alterations that occur in prostate cancer. Their data is now available to other researchers through a public Web site, and may be ripe for translation into more effective diagnostic tests and therapies.

In some cancer types, including breast and lung cancer, findings from genome projects have made it possible to classify tumors based on their genetic make-up and to make more informed treatment choices based on such classification. But until recently, genomic research had provided less understanding about the differences that exist among tumors of the prostate — some of which grow so slowly that patients never experience problems, while others are aggressive and lethal.

One reason is that the tumors, which often grow in small masses throughout the prostate, are notoriously difficult to isolate and analyze. In addition, since gene mutations are relatively rare in early prostate cancer, researchers need to examine other types of genomic features to assess whether early-stage tumors will quickly become life-threatening.

A decade ago, the late William L. Gerald (1954-2008), a surgical pathologist at Memorial Sloan Kettering, initiated a collection of high-quality tumor specimens obtained from prostate cancer patients who were treated surgically at Memorial Hospital — all of whom had consented to having their clinical history archived along with samples of their tumors.

In building and exploring this knowledge bank — which today is one of the largest of its kind for prostate cancer research — Dr. Gerald worked closely with a team of surgeons and medical oncologists. The team was led by Peter T. Scardino, Chair of the Department of Surgery. The group also included Victor Reuter, Vice Chair of the Department of Pathology. Later, they were joined by clinical and laboratory scientists led by Dr. Sawyers and Chris Sander, who chairs the Sloan Kettering Institute’sComputational Biology Program.

The researchers collected different types of information about genomic alterations in these tumors — including the DNA sequences of cancer-related genes, gene expression patterns, and gene copy numbers. (A cell normally contains two copies of each gene, but cancer cells often have extra or missing copies of some genes.)

When combining this information they discovered that, for some genes, extensive copy-number changes were characteristic of tumors that were destined to advance quickly.

Studies are now under way to explore if copy-number profiling might provide a new way to predict the course of a patient’s disease. The findings could lead to the creation of a genetic test to help determine whether or not a patient should be treated, Dr. Sawyers said.

The study has also invigorated hope for the development of new therapies. In analyzing their data, the researchers were able to identify several cellular processes, or pathways, that in many cases might drive prostate cancer progression. And such major pathways are believed to be the most suitable ones to explore as drug targets.

Pathway identification tends to require advanced computer science applications, Dr. Sander explained. “The problem with a disease like prostate cancer is that each tumor has a different genetic profile. So if we simply compare tumor samples gene by gene, very few single-gene common themes emerge,” he said, referring to themes in tumor biology that could point the direction for biomarker and therapy development and potentially be exploited in the clinic.

For this reason, he and his colleagues Nikolaus Schultz, Barry Taylor, and Ethan Cerami have developed a method called networkanalysis, in which a computer sifts through large amounts of genomic data and views it in light of what is known about genes and the way they interact in normal and cancerous cells. There is so much knowledge about the more than 20,000 human genes that “the human brain alone can no longer process all this information,” Dr. Sander said, “so use of advanced computer methods in cancer biology is now a necessity.”

Pathway analysis revealed, for example, that in nearly all metastatic prostate tumors, and a large fraction of primary ones, a variety of gene alterations had led to activating alterations of the androgenreceptor pathway. This observation might help researchers understand why certain types of drugs work in some patients and not in others, and develop more effective treatment strategies.

Dr. Sander noted that a genome project of this scope could not have been achieved without strong teamwork that transcends disciplines, “which is one of the things Memorial Sloan Kettering does best. It was wonderful to see such a diverse group of scientists and clinicians gather every other week to solve these complicated problems,” he recalls, “thanks to the initiative William Gerald took.”

aggressive (uh-GREH-siv)

In medicine, describes a tumor or disease that forms, grows, or spreads quickly. It may also describe treatment that is more severe or intense than usual.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

analysis (uh-NA-lih-sis)

A process in which anything complex is separated into simple or less complex parts.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

androgen (AN-droh-jen)

A type of hormone that promotes the development and maintenance of male sex characteristics.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

biomarker (BY-oh-MAR-ker)

A biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, or of a condition or disease. A biomarker may be used to see how well the body responds to a treatment for a disease or condition. Also called molecular marker and signature molecule.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

breast (brest)

Glandular organ located on the chest. The breast is made up of connective tissue, fat, and breast tissue that contains the glands that can make milk. Also called mammary gland.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

cancer (KAN-ser)

A term for diseases in which abnormal cells divide without control and can invade nearby tissues. Cancer cells can also spread to other parts of the body through the blood and lymph systems. There are several main types of cancer. Carcinoma is a cancer that begins in the skin or in tissues that line or cover internal organs. Sarcoma is a cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. Leukemia is a cancer that starts in blood-forming tissue such as the bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the blood. Lymphoma and multiple myeloma are cancers that begin in the cells of the immune system. Central nervous system cancers are cancers that begin in the tissues of the brain and spinal cord. Also called malignancy.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

cell (sel)

The individual unit that makes up the tissues of the body. All living things are made up of one or more cells.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

clinical (KLIH-nih-kul)

Having to do with the examination and treatment of patients.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

DNA

The molecules inside cells that carry genetic information and pass it from one generation to the next. Also called deoxyribonucleic acid.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

drug (drug)

Any substance, other than food, that is used to prevent, diagnose, treat or relieve symptoms of a disease or abnormal condition. Also refers to a substance that alters mood or body function, or that can be habit-forming or addictive, especially a narcotic.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

gene (jeen)

The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

gene expression (jeen ek-SPREH-shun)

The process by which a gene gets turned on in a cell to make RNA and proteins. Gene expression may be measured by looking at the RNA, or the protein made from the RNA, or what the protein does in a cell.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

genetic (jeh-NEH-tik)

Inherited; having to do with information that is passed from parents to offspring through genes in sperm and egg cells.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

genetic profile (jeh-NEH-tik PROH-file)

Information about specific genes, including variations and gene expression, in an individual or in a certain type of tissue. A genetic profile may be used to help diagnose a disease or learn how the disease may progress or respond to treatment with drugs or radiation.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

genome (JEE-nome)

The complete genetic material of an organism.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

L

A measure of volume for a liquid, using the metric system. One L is equal to 1,000 cubic centimeters (cc), 1,000 milliliters (mm), or 1.0567 quarts (qt). Also called liter.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

metastatic (meh-tuh-STA-tik)

Having to do with metastasis, which is the spread of cancer from the primary site (place where it started) to other places in the body.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

Network

A group of physicians, specialists, hospitals, outpatient centers, pharmacies, and other providers who has signed a contract with an insurance company to provide healthcare services to their subscribers.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

observation (OB-ser-VAY-shun)

In medicine, watching a patient’s condition but not giving treatment unless symptoms appear or change.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

pathologist (puh-THAH-loh-jist)

A doctor who identifies diseases by studying cells and tissues under a microscope.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

progression (pruh-GREH-shun)

In medicine, the course of a disease, such as cancer, as it becomes worse or spreads in the body.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

prostate (PROS-tayt)

A gland in the male reproductive system. The prostate surrounds the part of the urethra (the tube that empties the bladder) just below the bladder, and produces a fluid that forms part of the semen.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

prostate cancer (PROS-tayt KAN-ser)

Cancer that forms in tissues of the prostate (a gland in the male reproductive system found below the bladder and in front of the rectum). Prostate cancer usually occurs in older men.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

receptor (reh-SEP-ter)

A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

surgery (SER-juh-ree)

A procedure to remove or repair a part of the body or to find out whether disease is present. An operation.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

therapy (THAYR-uh-pee)

Treatment.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

translation (trans-LAY-shun)

In biology, the process by which a cell makes proteins using the genetic information carried in messenger RNA (mRNA). The mRNA is made by copying DNA, and the information it carries tells the cell how to link amino acids together to form proteins.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

tumor (TOO-mer)

An abnormal mass of tissue that results when cells divide more than they should or do not die when they should. Tumors may be benign (not cancer), or malignant (cancer). Also called neoplasm.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

will (wil)

A legal document in which a person states what is to be done with his or her property after death, who is to carry out the terms of the will, and who is to care for any minor children.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)